The major histocompatibility complex (MHC) plays key roles in controlling both adaptive and innate immune systems. In the adaptive immune system, both MHC class I and class II antigens recognize, bind and present peptides to cytotoxic and helper T-cells, respectively, and initiate cell-to-cell communication between antigen presenting cells and T-cells by forming immunological synapses and activating both subtypes of T-cells for both cellular and humoral immune systems. In addition, a number of gene clusters in this complex encode proteins which play important roles for antigen processing (proteosome subunit, LMP2 & 7, antigen transporter, TAP1 & 2, antigen loading for class I antigen, Tapasin, antigen loading for class II antigens, DM & DO molecules). In the innate immune system, both classical (HLA-A,-B,-C in human) and non-classical class I (HLA-E) antigens, plus class I-related molecules (MIC-A, -B) interact with natural killer (NK) receptors (Killer immunoglobulin-like receptor genes [KIR] and natural killer cell lectin-like receptors [NKG] antigens in human and Ly-49 and NKG antigens in mouse) and inhibit and activate NK-cell functions. In addition to the immunological importance, the MHC provides important tools to study molecular evolution. Extremely polymorphic features of both class I and class II antigens identified in most vertebrates provide numerous numbers of peptide binding grooves for MHC class I and II antigens in order to adapt various pathogens. Natural and balancing selections play pivotal roles to generate and maintain these polymorphisms.The nature of multigene clusters of the MHC genes also provides a number of theories to explain the genesis of the MHC. Also, paralogous chromosomal regions found in three other locations in human (chr. 6p21.3 for MHC, 9q33-34, 1, 19 for the others) and jawed vertebrates raises questions for the origin of the MHC.A large-scale sequencing project for the HLA has been launched and completed for the 3.6 Mb of the classical class I, II, & III regions to reveal the molecular history of this important gene complex, and has identified 224 tightly linked genes, including 128 expressed genes, and 96 pseudogenes. More recently, the MHC expands to 4.6 Mb, including five subregions: 1) extended class II (280 kb); 2) class II (700 kb); 3) class III (1000 kb); 4) class I (1600 kb); and 5) extended class I (1000 kb). In contrast of this large complex structure in HLA, the chicken MHC B-locus presents a "minimal essential MHC" disposition extending 92 kb and including 19 functional genes, raising questions about the structure of other MHC systems. Gene annotation of MHC regions in the domestic cat was completed and identified 202 possible coding regions by GENSCAN program. The feline MHC is located on a pericentromeric region of a long arm of chromosome B2 and was split into two regions by the break of the distal class I region and translocated to a subtelomeric region of the same B2 chromosome by a chromosome inversion. The first region spans 2.976 Mbp sequence, which encodes six classical class II antigens (three DRA and three DRB antigens), nine antigen processing molecules (DOA/DOB, DMA/DMB, TAPASIN, and LMP2/LMP7. TAP1/TAP2), twelve class I antigens (MHC_IA to MHC_IL), two class I related (MIC) molecules. The second region spans 0.362 Mbp sequence encoding no class I genes (in human HLA at least eleven class I genes in this HLA-A corresponding region) and only framework genes, including three olfactory receptor genes were found. In addition, three major feline endogenous retrovirus groups: FeLV-subtype A-like, ECE-RD114-like and, Porcine Leukemia virus-like sequences were found within a 100 Kbp interval in the middle of class I region on a percentromeric region of the long arm of chromosome B2. 2 x Cat Whole Genome Shotgun (WGS) Sequence Assembly was completed from DNA molecules isolated from an Abyssinian female cat, Cinnamon.